Currently, compounds having various chemical structures hold promise as medicines such as anticancer drugs or antiviral drugs, and are actually used for clinical treatment. However, among these, poorly water soluble drugs are known that have an extremely low solubility with respect to water despite having an extremely excellent pharmacological effect. There are cases in which, with respect to these poorly water soluble drugs, the administration method is restricted or clinical application in an appropriate concentration is difficult, and, in such a case, sufficient therapeutic effects may not be demonstrated.
For example, paclitaxel has excellent pharmacological activity as an anticancer drug and has recently been widely clinically used; however, in present circumstances, since the solubility of paclitaxel with respect to water is extremely low (the degree of solubility is 6 μg/mL or less), the administration method is restricted, and sufficient therapeutic effects are not obtained. Usually, when administering paclitaxel to cancer patients, paclitaxel is dissolved in physiological saline using polyoxyethylene castor oil and dehydrated ethanol as solubilizing agents, and then the solution thus obtained is administered by intravenous drip infusion over 3 hours.
Further, cases have been reported in which the above polyoxyethylene castor oil used as a solubilizing agent exhibits very serious side effects such as anaphylactic shock. Since surfactants are generally used in order to solubilize poorly water soluble drugs, the occurrence of side effects due to surfactants, as described above, should be avoided if at all possible. Therefore, not only reduction of the side effects of intravenous drip injection, but also improvement of the administration method is required, from the viewpoint of the quality of life (QOL) of the patients.
Meanwhile, in the case of orally administering paclitaxel, since the degree of solubility of paclitaxel is low, and further, since paclitaxel is discharged by P-glycoprotein in gastrointestinal epithelia, it is known that the bioavailability thereof is extremely low, being in the region 4% or less. Therefore, with regard to paclitaxel, further improvement has been deemed necessary in order to obtain a preparation for oral administration, which is most desirable from the viewpoint of enhancement of QOL.
In many types of poorly water soluble drugs other than paclitaxel as well, problems similar to those of paclitaxel are in evidence. Accordingly, enhancement of the solubility of poorly water soluble drugs with respect to water and improvement of the bioabsorption ratio are expected to make it possible to realize various kinds of drug therapy associated with poorly water soluble drugs.
From one such viewpoint, a copolymer (hereinafter, referred to as “Poly(MPC-co-BMA)”) having excellent biocompatibility, the copolymer being obtained by using 2-methacryloyloxy ethyl phosphoryl choline (hereinafter, referred to as “MPC”), which is a monomer having a phospholipid polar group, and n-butyl methacrylate (hereinafter, referred to as “BMA”), which is a hydrophobic monomer, has been developed (see, for example, Japanese Patent Application Laid-Open (JP-A) No. 3-3939) and has been commercialized under the trade name PUREBRIGHT (registered trademark; hereinafter in the present specification, the same applies.) by NOF Corporation.
Further, JP-A No. 2003-137816 discloses a method of solubilizing paclitaxel or the like using the above copolymer. It is described that it is possible to dissolve a poorly water soluble drug such as paclitaxel at a high concentration by using the solubilizing method described in the above document.
However, in the solubilizing method using the above copolymer, since heating is needed, there are concerns regarding the deterioration of the drug. Further, since this solubilizing method requires a large amount of the copolymer in order to enhance the solubility, although the degree of solubility is enhanced, the diffusibility of the drug is lowered, and thus, it is difficult to improve the membrane permeability and bioabsorbability of the drug. Therefore, for obtaining a preparation for oral administration, which is most desirable from the viewpoint of QOL, the bioavailability is insufficient, and further improvement is needed.